Diet therapy may provide a low cost alternative and/or adjuvant treatment to improve the care of veterans suffering from service-connected Multiple Sclerosis (MS). Botanicals are protective in MS animal models by modulating immune function and decreasing inflammation. Some also improve cognition and depression in animals, symptoms that are troublesome for the MS patient. Blueberries, in particular, can alter immune function, decrease inflammation and alter expression of proinflammatory cytokines, thought to be responsible for some of the sickness behavior, such as depression, fatigue and cognitive dysfunction, in MS. We have shown that dietary supplementation with whole, freeze-dried blueberry powder (WBBP) decreased by greater than 50%, the incidence of symptoms in a mouse model of MS and significantly improved symptoms in blueberry-fed mice that did get sick. We hypothesize that blueberry powder will have a dose-dependent effect in both preventing and ameliorating clinical and depressive symptoms in EAE mice. The following specific aims will be used to test this hypothesis: This proposal is designed to establish the therapeutic potential of blueberries as a prospective supplement to reduce the severity of symptoms in MS patients. This will be accomplished by testing whole blueberry powder in several different models of EAE to represent the heterogeneous nature of human MS. Further, we will determine whether the mechanism(s) of previously described blueberry protection involves alteration of immune cell effector function. Specifically, we will test the following hypothesis: blueberry supplementation shifts EAE immune response from a Th1 to a Th2 response with subsequent decrease in neuroinflammation. This hypothesis will be tested in three specific aims: Specific Aim 1: Determine whether blueberry protection in chronic EAE is a result of altered immune cell effector function. This aim will determine whether blueberry protection is a result of a shift from Th1 to Th2 T cell profiles including altered cytokine production. Specific Aim 2: Determine whether blueberry is protective in relapsing-remitting EAE. This aim will allow us to test the potential preventive and ameliorative properties of blueberry supplementation. Specific Aim 3: Determine whether blueberry protective effects are due to alterations in the NFkB:IkB signaling system. NFkB activation mediates inflammatory activation in microglia and astrocytes; this aim will allow us to determine NFkB involvement in blueberry neuroprotection. In summary, these studies are designed to determine whether there is potential for blueberries to be used as a supplement to reduce the severity of MS in humans. It is highly significant because of the lack of adequate current strategies to improve the quality of life for MS patients. Development of this novel diet therapy may provide significant direct and/or synergistic benefits in the treatment of MS at low cost with few side effects. These studies are of particular significance to potential treatment of MS since even the best pharmacological interventions have significant side effect and may interact with multiple other MS medications. However, diet therapy is easily administered, well tolerated and has few side effects.